Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer’s disease

The complex pathogenesis of Alzheimer’s disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evalua...

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Veröffentlicht in:	European journal of medicinal chemistry Jg. 219; S. 113426 - 113442
Hauptverfasser:	Zhou, Li-Cheng, Liang, Ying-Fan, Huang, Yi, Yang, Gui-Xiang, Zheng, Lu-Lu, Sun, Jia-Min, Li, Yang, Zhu, Fu-Li, Qian, He-Wen, Wang, Rui, Ma, Lei
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.07.2021 Elsevier
Schlagworte:	Alzheimer’s disease Anti-beta amyloid Antioxidant Chemistry, Medicinal Diosgenin Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology Diosgenin Alzheimer’s disease Antioxidant Anti-beta amyloid PATHOLOGIES OXIDATIVE STRESS MELATONIN TAU DIRECTED LIGANDS NEUROTOXICITY AMYLOID-BETA A-BETA SIMULATIONS Alzheimer's disease
ISSN:	0223-5234, 1768-3254, 1768-3254
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Abstract	The complex pathogenesis of Alzheimer’s disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ1-42 was −40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ1-42. The predicted values of brain/blood partition coefficient (−0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD. [Display omitted] •Design and synthesis of diosgenin-indole derivatives.•Biological evaluation and structure-activity relationships of these compounds.•H2O2, 6-OHDA and Aβ models were used to evaluate neuroprotective activity in vitro.•5b effectively ameliorated memory and learning impairments of Aβ-damaged mice.•5b is a new potential candidate for AD treatment.
AbstractList	The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ1-42 was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ1-42. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD.The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ1-42 was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ1-42. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD. The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H O (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H O (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ . The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å ) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H O . In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD. The complex pathogenesis of Alzheimer’s disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ1-42 was −40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ1-42. The predicted values of brain/blood partition coefficient (−0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD. [Display omitted] •Design and synthesis of diosgenin-indole derivatives.•Biological evaluation and structure-activity relationships of these compounds.•H2O2, 6-OHDA and Aβ models were used to evaluate neuroprotective activity in vitro.•5b effectively ameliorated memory and learning impairments of Aβ-damaged mice.•5b is a new potential candidate for AD treatment. The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and A beta (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 +/- 1.9%), 6-OHDA (38.4 +/- 2.4%) and A beta(1-42) (54.4 +/- 2.7%). Molecular docking study suggested the affinity for 5b bound to A beta(1-42) was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to A beta(1-42). The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 A(2)) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Abinjected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD. (C) 2021 Elsevier Masson SAS. All rights reserved.
ArticleNumber	113426
Author	Zheng, Lu-Lu Qian, He-Wen Liang, Ying-Fan Zhu, Fu-Li Yang, Gui-Xiang Ma, Lei Huang, Yi Sun, Jia-Min Li, Yang Zhou, Li-Cheng Wang, Rui
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Keywords	Diosgenin Alzheimer’s disease Antioxidant Anti-beta amyloid PATHOLOGIES OXIDATIVE STRESS MELATONIN TAU DIRECTED LIGANDS NEUROTOXICITY AMYLOID-BETA A-BETA SIMULATIONS Alzheimer's disease
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Snippet	The complex pathogenesis of Alzheimer’s disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents... The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents...
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SubjectTerms	Alzheimer’s disease Anti-beta amyloid Antioxidant Chemistry, Medicinal Diosgenin Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology
Title	Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer’s disease
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